This Pathway to Independence proposal (Sex differences in stress-alcohol interactions modulating amygdala activity) addresses how sex interacts with the stress response system to regulate the development of alcohol dependence and the propensity to relapse. This project will investigate the impact of sexual dimorphism in the amygdala, a stress- and reward-responsive brain region, on the severity of neuroadaptations following stressors (including withdrawal from chronic alcohol). I hypothesize that hyper-activation of the stress axis in females results in enhanced susceptibility to stress-induced neuroadaptations in the amygdala and thus heightened tendency to relapse. This project takes an innovative approach, combining slice electrophysiology (new training to be obtained during the mentored K99 phase of the award) with biochemistry and behavior to answer a pressing question in alcohol research: how does sex impinge on the interaction between stress and alcohol to generate sexually dimorphic neuroadaptations in stress-responsive brain regions thought to underlie alcohol dependence? This proposal will address one possible mechanism, involving the stress hormone corticosterone and the novel putative downstream effector PDE10A. Utilizing electrophysiology, biochemistry and behavioral techniques, I will investigate how these 3 factors (stress, alcohol and sex) interact to modulate transmission in glutamatergic projections from the basolateral (BLA) to the central nucleus (CeA) of the amygdala. I will also test the functionality of identified molecular adaptations in vio to ascertain their involvement in both traditional stress-induced reinstatement and stress history models. Indeed, the stress history model is quite novel, as I developed the paradigm for my postdoctoral NRSA, in order to study the long-term effects of stress history on alcohol self-administration. As female rats have not been studied in these relapse and reinstatement paradigms, this study will be a significant advance for the field of alcohol research even in isolation from delineation of the proposed the molecular mechanism. Together, these studies will integrate my past training in molecular neurobiology and behavior with essential new training in electrophysiology, providing me with the diversity of experience to investigate complete mechanisms underlying alcohol dependence - from molecule to circuit activity to regulation of alcohol intake. In addition, the mentorship I will receive from Drs. Roberto and Koob, as well as myriad career development opportunities, thanks to the excellent environment of TSRI and the greater San Diego scientific community, will greatly facilitate my transition to independence in a timely fashion and enhance my level of productivity as I establish myself as an independent investigator in the R00 phase of the award.